PDE IV is present in all the major inflammatory cells including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of inflammatory cell activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. Non-selective PDE inhibitors, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation. With this well-known distinction between PDE isozymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects associated with PDE inhibitors is apparent.
U.S. Pat. No. 5,804,588 discloses several quinoline 5-carboxamides as PDE IV inhibitors. A compound disclosed therein has the formula I:
The N-oxide of the compound of formula I is the compound of formula II, which is disclosed in U.S. Pat. No. 6,410,559. The '559 patent additionally discloses a process to synthesize the compound of formula II and analogs.
Furthermore, M. Billah et al, Bioorg. & Medicinal Chem., (2002), 12, 1621–1623, disclose the compound of formula I as well as its N-oxide, the compound of formula II.
M. Billah et al, Bioorg. & Medicinal Chem., (2002), 12, 1617–1619, describe a process to synthesize the compounds of formulas I and II. The synthesis which goes through the compound of formula III:
involves several tedious steps and necessitates the use of expensive starting materials and the use of a palladium catalyst. Removal of the palladium catalyst is generally difficult as is known to those skilled in the art.
Attention is also drawn to M. Marull et al, Eur. J. Org. Chem, (2003), 1576–1588, and F. Cottet and M. Marull et al, Eur. J. Org. Chem, (2003), 1559–1568, respectively describing the synthesis of certain quinolinones and recommendable routes to trifluoromethyl-substituted quinoline carboxylic acids.
There remains a need for new, economical methods of making PDE IV inhibitors based on quinoline carboxamide structure. This invention provides a process to prepare such quinoline compounds carrying a trifluoromethyl group at the 2-position and having a substituent at the 8-position of the quinoline moiety.